Intestinal Absorption Of Cd Research Articles

Toxicity Tolerance in the Carcinogenesis of Environmental Cadmium.

Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted.

Sex-dependent effects of rice cadmium exposure on body weight, gut microflora, and kidney metabolomics based on a mouse model

Consumption of cadmium (Cd) contaminated rice is the main dietary source of Cd exposure and toxicity. To protect humans from Cd toxicity, it is pivotal to fully understand the sex-dependent toxicity of subchronic rice-Cd exposure. However, the sex-dependent effects of subchronic rice-Cd exposure on body weight gain, gut microflora, and kidney metabolomics are still unclear. In this study, a Cd-free and a Cd-contaminated rice (0.005 and 0.74 mg Cd kg−1) were fed to both female and male mice for one month, with changes in body weight gain, Cd accumulation in tissue, bone mineral concentration, expression of intestinal channels involving in Cd and calcium (Ca) absorption, gut microbiota, and kidney metabolites assessed for both genders. Results showed that female mice had normal body weight gain after rice-Cd exposure, while body weight of male mice was decreased from 19.8 to 17.5 g over the one-month consumption of the Cd-contaminated rice (0.74 mg kg−1), suggesting specific toxicity on growth of male mice. Rice-Cd exposure had limited effects on gut microbiota for both genders. However, higher Cd accumulation in liver and femur was observed in male mice than in females, which may be due to higher intestinal expression of Ca channels involving in intestinal Cd absorption in male mice with rice-Cd exposure. Greater risk of osteoporosis was also observed in male mice. In addition, kidney metabolomic profiling showed special disruption of adrenocortical hormone homeostasis for male mice with rice-Cd exposure. Particularly, expression of cortisol in kidneys of male mice was elevated 37.1-fold with rice-Cd exposure, likely resulting in Cushing's syndrome and contributing to growth retardation. This study advances our understanding of the sex-dependent toxicity of rice-Cd exposure, and highlights the priority of protecting males from the adrenocortical hormone disrupting effects of rice-Cd exposure.

Cadmium oral bioavailability is affected by calcium and phytate contents in food: Evidence from leafy vegetables in mice

To test high cadmium (Cd) concentration may not be high in health risk when considering Cd bioavailability, we assessed variation of Cd relative bioavailability (RBA, relative to CdCl2) using a mouse assay for 14 vegetables of water spinach, amaranth, and pakchoi. Cadmium concentration varied from 0.13 ± 0.01–0.37 ± 0.00 μg g–1 fw. Cadmium-RBA also varied significantly from 22.9 ± 2.12–77.2 ± 4.46%, however, the variation was overall opposite to that of Cd concentration, as indicated by a strong negative correlation between Cd-RBA and Cd concentration (R2 = 0.43). Based on both Cd concentration and bioavailability, the identified high-Cd pakchoi variety resulted in significantly lower Cd intake than the high-Cd varieties of water spinach and amaranth (4.74 ± 0.05 vs. 10.1 ± 0.54 and 8.03 ± 0.04 μg kg–1 bw week–1) due to significantly lower Cd-RBA (22.9 ± 2.12 vs. 77.2 ± 4.46 and 51.3 ± 2.93%). The lower Cd-RBA in pakchoi was due to its significantly higher Ca and lower phytate concentrations, which facilitated the role of Ca in inhibiting intestinal Cd absorption. This was ascertained by observation of decreased Cd-RBA (90.5 ± 12.0% to 63.5 ± 5.53%) for a water spinach when elevating its Ca concentration by 30% with foliar Ca application. Our results suggest that to assess food Cd risk, both total Cd and Cd bioavailability should be considered.

Involvement of metal transporters in the intestinal uptake of cadmium.

We investigated the mechanism underlying intestinal cadmium (Cd) uptake based on the mediators (metal transporters) of essential elements, such as Fe, Zn, Cu, and Ca, under normal conditions in female rats. These elements interact with Cd uptake from the intestinal tract. Cd concentration at each site of the small intestine (duodenum, jejunum, and ileum) increased as Cd exposure increased. However, Cd concentration was the highest in the duodenum. The gene expression of ZIP14, DMT1, and ATP7A increased with increase in Cd concentration. Further, Cu concentration decreased as Cd concentration increased. In contrast, Fe concentration displayed a decreasing tendency with the increase in Cd concentration. The gene expression levels of ZIP14, DMT1, and ATP7A were positively correlated with Cd concentration. Immunohistochemical staining revealed the positive sites of ZIP14 and DMT1 scattered in the area adjacent to the goblet cells, resorbable epithelial cells, and lamina propria in the duodenum tissue, according to the increase in Cd concentration. Cd is induced to synthesize and bind to metallothionein (MT-I and -II) and accumulate in the intestinal tissues, mainly in the duodenum. Such findings suggest that Cd, a contaminant element, is taken up from the intestinal tract by multiple metal transporters such as Cu, Fe, and Zn, thereby involving in the intestinal Cd absorption.

Concentration-dependent roles of DMT1 and ZIP14 in cadmium absorption in Caco-2 cells.

Intestinal absorption of cadmium (Cd) is considered to be mediated mainly by the ferrous iron transporter DMT1, or the calcium transporter CaT1. The roles of zinc transporters such as ZIP8 and ZIP14 remain unclear, and the roles of these four transporters in the intestinal uptake of Cd under physiological conditions have not been compared. Here, we used a trans-well cell culture system to investigate the effects of the down-regulation of these four transporters on the uptake of Cd from the apical side of enterocytes. We used a Caco-2-kh cell line that can form tight junctions within a few days. The transfection of DMT1 siRNA significantly decreased the Cd uptake from the apical side at 5 μM, but not at 0.1 or 1 μM. The transfection of ZIP14 siRNA markedly decreased the Cd uptake at 0.1 and 1 μM, but not at 5 μM. The transfection of siRNA of CaT1 or ZIP8 did not alter the Cd uptake at any concentrations of Cd examined. These results suggest that DMT1 and ZIP14 play different roles in intestinal Cd absorption depending on the concentration of Cd.

How Does Contamination of Rice Soils with Cd and Zn Cause High Incidence of Human Cd Disease in Subsistence Rice Farmers

Rice (Oryza sativa L.) grown on Zn mine waste contaminated soils has caused unequivocal Cd effects on kidney and occasional bone disease (itai-itai) in subsistence rice farmers, but high intake of Cd from other foods has not caused similar effects. Research has clarified two important topics about how Cd from mine waste contaminated rice soils has caused Cd disease: (1) bioaccumulation of soil Cd into rice grain without corresponding increase in Zn, and (2) subsistence rice diets potentiate Cd absorption/bioavailability and risk to farm families. Absorption of Cd by rice roots occurs on the NRAMP5 Mn2+ transporter. Although other transporters can influence Cd uptake-transport to shoots and grain, making NRAMP5 null greatly reduces grain Cd. Zn2+ has little ability to inhibit Cd2+ transfer in rice but clearly inhibits Cd uptake in other plant species. The bioavailability of dietary Cd is increased for subsistence rice diets. Research has identified that low levels and bioavailability of Zn and Fe in polished rice grain cause upregulation of Cd absorption on the Fe2+ transporter of duodenum cells (DMT1). Added dietary Zn can also inhibit intestinal Cd absorption somewhat. Nutritional stress (Fe, Zn deficiency) in humans consuming subsistence rice diets thus promotes Cd accumulation and adverse effects. No other dietary (crop) Cd exposure has caused unequivocal Cd-induced renal proximal tubular dysfunction (the first adverse Cd effect) in humans. Recognition of the very unusual nature of Cd risk from rice compared to other crops should be taken into account in setting international limits of Cd in rice and other foods.

Protective effects of Lactobacillus plantarum CCFM8610 against chronic cadmium toxicity in mice indicate routes of protection besides intestinal sequestration.

Our previous study confirmed the ability of Lactobacillus plantarum CCFM8610 to protect against acute cadmium (Cd) toxicity in mice. This study was designed to evaluate the protective effects of CCFM8610 against chronic Cd toxicity in mice and to gain insights into the protection mode of this strain. Experimental mice were divided into two groups and exposed to Cd for 8 weeks via drinking water or intraperitoneal injection. Both groups were further divided into four subgroups, control, Cd only, CCFM8610 only, and Cd plus CCFM8610. Levels of Cd were measured in the feces, liver, and kidneys, and alterations of several biomarkers of Cd toxicity were noted. The results showed that when Cd was introduced orally, cotreatment with Cd and CCFM8610 effectively decreased intestinal Cd absorption, reduced Cd accumulation in tissue, alleviated tissue oxidative stress, reversed hepatic and renal damage, and ameliorated the corresponding histopathological changes. When Cd was introduced intraperitoneally, administration of CCFM8610 did not have an impact on tissue Cd accumulation or reverse the activities of antioxidant enzymes. However, CCFM8610 still offered protection against oxidative stress and reversed the alterations of Cd toxicity biomarkers and tissue histopathology. These results suggest that CCFM8610 is effective against chronic cadmium toxicity in mice. Besides intestinal Cd sequestration, CCFM8610 treatment offers direct protection against Cd-induced oxidative stress. We also provide evidence that the latter is unlikely to be mediated via protection against Cd-induced alteration of antioxidant enzyme activities.

Characterization of basolateral-to-apical transepithelial transport of cadmium in intestinal TC7 cell monolayers

Cadmium (Cd) is a toxic metal with an extremely long half-life in humans. The intestinal absorption of Cd has been extensively studied but the role the intestinal epithelium may play in metal excretion has never been considered. The basolateral (BL)-to-apical (AP) transepithelial transport of Cd was characterized in TC7 human intestinal cells. Both AP and BL uptakes varied with days in culture, and BL uptake was twofold higher compared to AP in differentiated cultures. A 50% increase in the BL uptake of 0.5 μM (109)Cd was observed at pH 8.5 in a chloride but not nitrate medium, suggesting the involvement of a pH-sensitive mechanism of transport for chloro-complexes. Fe and Zn inhibited the BL uptake of Cd whereas complexation by albumin had no effect, but the stimulatory effect of pH 8.5 was lost in the presence of albumin. The BL uptake of [(3)H]-MPP(+) and (109)Cd were both inhibited by decynium22 without reciprocal inhibition. MRP2 and MDR1 mRNA levels increased as a function of days in culture. A 25 and 20% decrease in the cellular AP efflux of Cd was observed in the presence of verapamil and probenecid, respectively. In cells treated with BSO, which lowered by 26% the total cellular thiol content, the inhibitory effect of verapamil increased, whereas that of probenecid decreased. These results reveal the existence of a decynium22-sensitive mechanism of transport for Cd at the BL membrane, and suggest the involvement of MDR1 and MRP2 in cellular Cd efflux at the AP membrane. It is conceivable that the intestinal epithelium may contribute to Cd blood excretion.

Increased Hepatic Accumulation of Ingested Cd is Associated with Upregulation of Several Intestinal Transporters in Mice Fed Diets Deficient in Essential Metals

Essential metals (EMs) can affect the metabolism of nonessential metals. It has been suggested that Fe deficiency increases intestinal absorption of Cd via divalent metal transporter 1 (DMT1). To investigate whether EM nutritional status is a host risk factor for Cd accumulation, we studied the effect of nutritional status of Ca, Cu, Mg, Zn, and Fe that most often ingested by humans at levels below recommended dietary allowances on tissue accumulation of orally administered Cd. Mice were divided into groups and given different EM-deficient (EMDF) diets (CaDF, CuDF, MgDF, ZnDF, or FeDF) for 4 weeks. EMDF mice had significantly (p < 0.05) lower plasma or hepatic concentrations of the deficient EM than did mice receiving control diets. Hepatic Cd accumulation was significantly (p < 0.05) increased after oral Cd administration in all EMDF mice, but not in any EM-supplemented mice. Intestinal expression of mRNAs for the Fe-transporters DMT1 and ferroportin was increased in FeDF mice, but not in other EMDF mice, causing an increase in hepatic Fe concentration. Similarly, intestinal expression of mRNA for calcium transporter 1 was significantly increased in CaDF mice, but not in other EMDF mice. These results suggest that DMT1 is not the sole transporter of Cd, and that Cd is absorbed and accumulated through multiple pathways that maintain EM homeostasis in EMDF condition. Therefore, EM nutritional status is a risk factor for increasing hepatic accumulation of ingested Cd.

Normal cadmium uptake in microcytic anemia mk/mk mice suggests that DMT1 is not the only cadmium transporter in vivo

Divalent metal transporter 1 (DMT1) is a mammalian iron (Fe) transporter and also transports Cadmium (Cd) in vitro. This study compared Cd absorption in DMT1-dysfunctional MK/Rej- mk / mk mice ( mk/mk mice) and in DMT1-functional, Fe-deficient wild-type (WT) mice, to clarify the role of DMT1 in intestinal Cd absorption in vivo. Mice were given 1 ppm CdCl 2 aq in drinking water for 2 weeks, and the concentrations of Cd and Fe in liver, kidney, and intestinal epithelium were subsequently determined. The Fe concentration in intestinal epithelia of WT mice was decreased in proportion to the level of dietary Fe limitation, while Cd accumulation under the same conditions was increased. DMT1 mRNA expression in the small intestine of Fe-deficient WT mice was clearly increased compared to that in Fe-sufficient WT mice. Iron deficiency resulted in up-regulation of Cd uptake in the intestine of Fe-deficient WT mice. The mk/mk mice have a mutation in DMT1 and loss of its function led to decreased intestinal Fe concentration. However, intestinal Cd accumulation was the same as in WT mice and it was also increased in Fe-deficient situation. There is the possibility that an unknown Cd pathway has taken a role on Cd intestinal absorption in vivo and that this pathway is regulated by food Fe concentrations. Therefore, DMT1 is not the sole transporter of intestinal cadmium absorption in vivo.

Involvement of intestinal calcium transporter 1 and metallothionein in cadmium accumulation in the liver and kidney of mice fed a low-calcium diet

Essential metals can affect the metabolism of nonessential metals. Calcium (Ca) is an essential mineral that is commonly lacking in the diet. When we fed 5-week-old male mice for 4 weeks on a purified diet containing 0.005% Ca (CaDF mice), the Ca concentration in the plasma, liver and kidneys did not decreased. Cd accumulation increased in the liver and kidneys of CaDF mice given 1 mg/kg Cd orally each day for 5 days, but not in those given intraperitoneal injections of Cd or Cd-metallothionein (Cd-MT). The zinc (Zn) concentration increased significantly in the intestinal cytosol and plasma during the time the mice were fed the low-Ca diet, and expression of both MT-1 and ZnT-1 sharply increased with a similar time course. Intestinal mRNA expression of CaT1, a Ca transporter, was more than 10 times higher in CaDF mice than in controls, although expression of other transporters, including DMT1, decreased in CaDF mice. These results suggest that CaT1 may stimulate the intestinal absorption of Cd and Zn, and some Cd may be distributed to the kidneys along with MT induced by Zn.

Jejunal transfer rates of 109cadmium chloride increase in rats in vitro and in vivo after oral pretreatment with cadmium or zinc chloride

An increased body retention of Cd in rats orally pretreated with Cd or Zn is explained by induction of hepatic and renal metallothionein. Whether intestinal absorption of Cd increases after such treatments is not clear yet. To approach this problem we measured jejunal transfer rates of 109Cd in vitro and in vivo in pretreated rats (0.44 mmol Cd/l or 4.6 mmol Zn/l in the drinking water for 10 days) and compared them with those of untreated controls. Isolated jejunal segments were used for in vitro perfusion. In vivo perfusion was performed in anaesthetized rats with blood collected from mesenteric venules substituting corresponding losses by reinfusion of rat blood. Water and glucose transfer did not differ between controls and pretreated rats. At a luminal concentration of 5 μmol 109CdCl 2/l, Cd and Zn pretreatment significantly increased the transfer rate of 109Cd in vitro and in vivo similarly. The 109Cd transfer rates in controls in the final perfusion intervals (80–120 min) were 0.06 (pmol/cm/min) in vivo and 0.05 in vitro; the corresponding rates in Cd or Zn pretreated rats were significantly higher ( P<0.05) and amounted to 0.11 and 0.18 or 0.15 and 0.23, respectively. Mucosal concentrations of 109Cd measured at the end of the perfusion period tended to be lower in the pretreated animals than in the controls. This suggests that pretreatment with Cd or Zn reduces the amount of 109Cd bound to the tissue leaving more 109Cd for the transfer step. As compared to a level of mucosal metallothionein of 8 μg/g wet weight in controls, increased amounts of 67 or 52 μg/g wet weight in the Cd or Zn pretreated rats, respectively, thus did not decrease but increased transfer rates of 109Cd. Therefore, increased small intestinal transfer rates of Cd can contribute to increase the body retention of Cd seen after oral pretreatment with Cd or Zn.

Intestinal absorption of cadmium is associated with divalent metal transporter 1 in rats.

The intestinal absorption of cadmium (Cd) increases when the body iron (Fe) stores are depleted. The depletion of Fe upregulates the expression of divalent metal transporter 1 (DMT1), which is located at the apical membrane of enterocytes lining the small intestine. DMT1 has been shown to transport Fe and other divalent metal ions in vitro. However, it is not known whether DMT1 mediates the intestinal absorption of Cd. To investigate DMT1 involvement in Cd absorption, rats were fed a diet for 4 weeks either deficient in Fe (FeD diet, 2-6 mg Fe/kg) or supplemented with Fe (FeS diet, 120 mg Fe/kg), followed by a single oral administration of 109 CdCl2. Body Fe status, hemoglobin, and tissue Cd concentration were determined at 48 h after Cd administration. Also, DMT1 mRNA levels were quantified in duodenum, kidney, and liver by the branched DNA signal amplification method. Animals fed the FeD diet exhibited a reduced body weight gain, depletion of body Fe, and Fe deficiency anemia. Tissue Cd concentration was significantly higher in FeD than in FeS diet-fed rats, especially in the duodenum. The amount of Cd retained in the body was 10-fold higher in rats fed the FeD diet than in those fed the FeS diet. DMT1 mRNA was highly expressed in duodenum and was 15-fold higher in the FeD diet group. The levels of DMT1 mRNA were significantly lower in kidney and liver than in duodenum, but were 30 and 40% higher, respectively, in rats fed the FeD diet than in rats fed the FeS diet. These findings suggest that functional DMT1 protein is likely upregulated in the small intestine at the mRNA level by body iron depletion and increases Cd uptake from the gastrointestinal tract with subsequent transfer of Cd to the circulation and body tissues. Furthermore, the data from this study may indicate that DMT1 is a nonspecific metal transporter, which can transport not only Fe, but probably the toxic metal as well.

The influence of humic substances on the absorption and distribution of cadmium in mice.

The complex binding of cadmium ions to humic and fulvic acids in water may influence the absorption and distribution of drinking-water Cd in humans. Thus, in the present study mice were given a single oral dose of Cd (109CdCl2, 25 microg/l) in 100 microl Millipore water containing different concentrations of humic compounds (0, 1, 10 and 100 mg dissolved organic carbon/l). The complex binding of Cd was studied by dialysis. At neutral pH, 1 mg dissolved organic carbon/l caused complex binding of more than 50% of the Cd, whereas more than 90% of Cd was bound at 10 and 100 mg dissolved organic carbon/l. At pH 3 the complex binding of Cd decreased somewhat, but over 90% of the Cd was bound at 100 mg dissolved organic carbon/l. Complex binding of Cd increased the lipid solubility of Cd, expressed as an octanol/ water partition coefficient, Nevertheless, more than 99% of the bound Cd was present as hydrophilic binding forms. Irrespective of the bound of Cd, the intestinal uptake and intracellular distribution (gel filtration on Sephadex G-75 column) were not affected by the humic substances 6 hr after dosage. Moreover, complex binding did not influence the intestinal absorption of Cd 24 hr after exposure. The median Cd retention in the kidneys of the 100 mg dissolved organic carbon/l group was 23% and 46% lower than that of the control group 6 and 24 hr after administration, respectively, indicating alterations in the distribution of Cd after absorption. Thus humic substances may affect the metabolism of toxic heavy metals, such as Cd, in vivo in mice, indicating that the presence of humic and fulvic acids in drinking water should be considered in future risk assessments of metals in drinking water.

Small-intestinal absorption of cadmium and the significance of mucosal metallothionein.

1 Although food intake is among the most important routes of Cd exposure, not many details are known about the intestinal absorption mechanisms of Cd. In this respect Cd is representative of most other nonessential, merely toxic metals. 2 Based on a concept of two distinguishable steps, intestinal absorption of Cd is characterized by high accumulation within the intestinal mucosa and a low rate of diffusive transfer into the organism. 3 After uptake into the mammalian organism, Cd is sequestered into hepatic metallothionein (MT). It is assumed that hepatic Cd-MT then gradually redistributes Cd to the kidney, which is the main target organ for chronic Cd toxicity. 4 When feeding low levels of dietary CdCl2, however, Cd accumulates preferentially in the kidney and to a lesser degree in the liver, a distribution pattern also found after intravenous and peroral administration of the Cd-MT complex itself. As dietary Cd induces intestinal MT, intestinal Cd-MT complexes could be at least partly responsible for the renal accumulation of dietary Cd. 5 For this mechanism, however, serosal release of mucosal Cd-MT is required. In fact, in vitro findings in rats reveal a concentration-dependent release of intestinal MT to the serosal side of the small intestine. These results indicate that endogenous intestinal MT may deliver Cd-MT to other inner organs, thus contributing to the preferential renal accumulation of ingested Cd.

The involvement of metallothionein in the intestinal absorption of cadmium in mice

Female mice were exposed to a single dose of 0.005 to 5 μg Cd/kg body wt., in order to test the hypothesis that once the Cd-binding capacity of intestinal metallothionein is saturated. Cd becomes more readily available for transfer from the mucosa to the circulatory system, causing an increase in Cd absorption. In this case the binding of Cd to MT would act as a barrier against Cd absorption, thus protecting the organism from accumulation and toxic effects of Cd in target organs such as the kidney. In mice the fractional Cd uptake (% of dose) in the duodenum, which was the main site of Cd uptake in the intestine, was not influenced by the Cd dose 6 h after dosage. However, the percentage of cytosolic Cd associated to MT in the duodenum decreased when the Cd dosage increased from 0.005 or 0.025 μg/kg to 5 μg/kg. Concomitantly, the percentage bound to low-molecular-weight (LMW) ligands increased, indicating saturation of the Cd-rmbinding capacity of MT. Nevertheless, the fractional absorption was not dosage dependent in the dosage interval studied. Moreover, there was no statistically significant correlation between the percentage of cytosolic Cd bound to MT and the percentage of Cd absorbed. Thus, our results do not support the hypothesis that the intestinal Cd absorption is increased when the Cd-binding capacity of intestinal MT is saturated.

Fulvic and humic acids decrease the absorption of cadmium in the rat intestine.

Dissolved organic carbon (DOC) in drinking water is mainly composed of fulvic and humic acids, which may form complexes with metal ions. The influence of DOC on the intestinal absorption of Cd in the rat was investigated using an "isolated intestinal segment" technique in anaesthetised rats. The lumens of segments were exposed for 60 min to different concentrations of CdCl2 and DOC in intact animals. The fractional absorption (FA) was not dose dependent in the dosage interval 0.01-0.03 microgram Cd/kg. However, at 15 and 150 micrograms Cd/kg both FA and intracellular Cd distribution in the segments were dose dependent, which is in line with results from other studies performed on similar experimental models. In the presence of 1 and 10 mg DOC/l, FA of Cd was just half as high as FA in animals that received Cd alone (0.01 microgram/kg). Moreover, a higher percentage of Cd was associated with the metallothionein fraction in the intestinal segment of the DOC-dosed rats. An in vitro speciation experiment showed that only 0.2-7.9% of the Cd in the incubation solution was complexed to DOC. In deionized water, however, more than 99% of the Cd was complexed to DOC. This result indicates that the incubation solution contained substances that negatively affect complexation of Cd to DOC. Mechanisms other than complexation of Cd to DOC in the intestinal lumen may therefore be involved in the inhibitory effect of DOC on the absorption of Cd.

Effects of mucosal metallothionein in small intestine on tissue distribution of cadmium after oral administration of cadmium compounds

The effect of mucosal metallothionein (MT) preinduced by zinc (Zn) on tissue distribution of cadmium (Cd) after administration of Cd with several chelating agents was studied in rats. After Cd-cysteine (Cd-Cys) was incubated with intestinal Zn-MT in vitro, all the Cd dissociated from Cys and exchanged the Zn bound to MT. However, dissociation of Cd bound to EDTA (Cd-EDTA) was not observed in the incubation mixture containing intestinal Zn-MT. The concentration of Cd in intestinal mucosa reached a maximum 16 hr after oral administration of Cd-Cys. The Cd level in the intestine was higher than that in the liver and kidney and was similar to that occurring after oral administration of CdCl 2. The amount of Cd distributed to the liver and kidney after Cd-EDTA administration was about 30% of the level after CdCl 2 administration. Even at 15 mg Cd/kg Cd-EDTA, the Cd level in the intestinal mucosa reached a plateau after 2–4 hr, as it did in the liver and kidney. When Cd-Cys was administered po to control or to Zn-pretreated rats, it was found that Zn pretreatment increased the concentration of Cd in the kidney, as was the case after oral administration of CdCl 2. This effect of Zn pretreatment was not observed after oral administration of Cd-EDTA. When Cd-MT was injected into the duodenum, the intestinal absorption of Cd was 60% of that after CdCl 2 administration. After the duodenal administration of Cd-MT, at all doses, the concentration of Cd in the kidney was higher than that in the liver. These results suggest that mucosal MT in the small intestine might trap Cd absorbed from the intestinal lumen and transport it to the kidney.

Dosage-dependent absorption of cadmium in the rat intestine measured in situ

Previous studies have shown that the disposition of cadmium (Cd) following oral administration is dosage dependent and may possibly be due to dosage-dependent intestinal absorption of Cd. Though extensively studied, the precise nature of Cd absorption by the intestine remains unclear. Similarly, the role of metallothionein (MT) in the intestinal absorption of Cd remains equivocal. The present study was designed (1) to characterize the intestinal absorption of Cd in the rat, and (2) to determine the role of MT in intestinal Cd absorption. The study has been conducted with an isolated intestinal loop preparation in situ, which allows direct measurement of intestinal absorption under nearly physiological conditions. Under urethane-induced anesthesia, Cd (0.1, 10, 100, 1000, or 10,000 μg/kg) was injected intraluminally into the isolated intestinal loop in situ and all mesenteric venous (portal) blood exiting from the loop was collected for 90 min. Absorption of Cd into the portal circulation was low at all dosages studied. The percentage of the dosage absorbed ranged from 0.09% at the 0.1 μg/kg dosage to 3.4% at the 10,000 μg/kg dosage. At low dosages (0.1 and 10 μg/kg), little difference was noted in the fractional absorption of Cd (0.09 and 0.14% of the dosage, respectively). However, the fractional absorption of Cd was 10-fold greater in rats administered 100 μg Cd/kg (1.1% of the dosage). Administration of higher dosages of Cd (1000 and 10,000 μg/kg) further increased the percentage of the dosage absorbed (1.8 and 3.4%, respectively). To evaluate the role of MT in the intestinal absorption of Cd, rats were subcutaneously injected with zinc (Zn) for 4 days (30 mg/kg/day) and the absorption of an intermediate dosage of Cd (100 μg/kg) was subsequently assessed in situ. Zn pretreatment increased the endogenous concentration of MT in the intestine 25-fold. Following intraluminal administration, 93% of Cd in intestinal cytosol of Zn-treated rats was bound to MT whereas 40% of the cytosolic Cd was bound to MT in saline-treated (control) rats. Moreover, the amount of Cd in intestinal cytosol was 2-fold greater in Zn-treated rats than in control rats. However, the intestinal absorption of Cd in rats pretreated with Zn demonstrated no difference from that in saline-treated rats. These results indicate that the intestinal absorption of Cd is dosage independent at low dosages of Cd (<10 μg/kg) and dosage dependent at high dosages (> 10 μg/kg). Furthermore, saturation of intestinal MT is not a major determinant of the observed dosage-dependent absorption of Cd.

Role of mucosal metallothionein preinduced by oral Cd or Zn on the intestinal absorption of a subsequent Cd dose.

Intestinal absorption of Cd is one of the main channels of Cd entry into the body leading to systemic toxicity. When Cd is absorbed, it first comes into contact with the gastrointestinal mucosa, particularly the duodenum mucosa. Therefore, the mucosal behavior of Cd is one of the most important factors, not only for determining the absorption rate, but also as concerns the interactions between Cd and other metals.